Blocking Uncontrolled Calcium Flux Protects the Brain from Stroke Damage

Preventing the binding of a proapoptotic enzyme during stroke (cerebral ischemia) protected the brain from damage caused by the unregulated transport of calcium ions into nerve cells.

Investigators at the University of Central Florida (Orlando, USA) and their collaborators at Louisiana State University (New Orleans, USA) worked with a mouse stroke model. They focused their efforts on understanding the role of an enzyme called death-associated protein kinase 1 (DAPK1), which was known to be a positive mediator of gamma-interferon induced programmed cell death.

The Investigators found that under the traumatic conditions induced by a stroke DAPK1 attached to and blocked the activity of NMDA (N-methyl-D-aspartate) receptors that normally control calcium flux in nerve cells. Lacking NMDA receptor control, nerve cells became overloaded with calcium and died.

To prevent damage from calcium overload the investigators resorted to two different types of therapy. In one study, they used gene-silencing techniques to eliminate DAPK1 from nerve cells. In another, they treated brain tissue with a soluble polypeptide, NR2BCT, which mimicked the region of the NMDA receptor that binds DAPK1. The peptide bound to DAPK1 more efficiently and prevented the enzyme from attaching to the NMDA receptor. In both cases, the treatment protected brain cells against stroke injury, and did not affect the normal physiological functions of the receptors.

Results published in the January 22, 2010, issue of the journal Cell confirmed that DAPK1 physically and functionally interacted with the NMDA receptor NR2B subunit at extrasynaptic sites, and this interaction acted as a central mediator for stroke damage.

"It is conceivable that this study not only provides new insights into the cellular and molecular basis responsible for stroke damage, but also provides a therapeutic target for stroke therapy," said senior author Dr. Youming Lu, professor of neurosciences at Louisiana State University.

Related Links:
University of Central Florida
Louisiana State University